p-Hydroxymandelic acid

ABSTRACT

A process for the isolation of a solid salt of p-hydroxymandelic acid, which process comprises reacting phenol with glyoxylic acid in the presence of sodium or potassium hydroxide, acidifying to a pH less than 3, extracting the resulting solution with a water-immiscible solvent to provide a solution of p-hydroxymandelic acid and precipitating the salt therefrom.

This invention relates to a chemical process, and in particular to aprocess for the isolation of a salt of p-hydroxymandelic acid. It alsorelates to novel salts which may be isolated by this process.

Salts of p-hydroxymandelic acid are valuable intermediates, for examplefor the preparation of p-hydroxyphenylglycine, which is useful for themanufacture of the penicillin derivative, amoxycillin.

British Pat. Specification No. 1,377,243 discloses in Example 5(b)thereof the preparation of a solution of the sodium salt ofp-hydroxymandelic acid (referred to therein as 4-hydroxyphenylglycolicacid), but this salt is not isolated.

One method for the isolation of the salt is disclosed in Belgium Pat.No. 867,287 which describes a process for the manufacture of solidsodium or potassium p-hydroxymandelate monohydrate which comprisesreacting by known means phenol with glyoxylic acid in the presence of,respectively, sodium or potassium hydroxide, followed by adjustment ofthe pH of the solution to between 5 and 7 and salting out of the desiredsodium or potassium salt with respectively, a sodium or potassium saltof a simple acid.

We have now found an advantageous method for the isolation of solidsalts of p-hydroxymandelic acid prepared in this way, by precipitationfrom an organic solution of the acid. This method of isolation producesa higher yield of isolated salt than the method described in BelgiumPat. No. 867,287.

Accordingly the present invention provides a process for the isolationof a solid salt of p-hydroxymandelic acid, which process comprisesreacting phenol with glyoxylic acid in the presence of sodium orpotassium hydroxide, acidifying to a pH less than 3, extracting theresulting solution with a water-immiscible solvent to provide a solutionof p-hydroxymandelic acid and precipitating the salt therefrom.

The reaction between phenol and glyoxylic acid may be carried out in anyconvenient way. Suitable conditions described in Belgium Pat. No.867,287 and also in Example 5(b) of British Pat. No. 1,377,243. Suitablythe reaction is carried out at a temperature in the range 20°-100° C.,suitably 20°-60° preferably 30°-40° C. We have found that it is alsopreferable to adjust the dilution of the reaction solution so that theconcentration of glyoxylic acid is in the range 3 to 9% w/v, preferably3.5 to 7%, especially 3.5 to 4.5% w/v. The reaction may advantageouslybe carried out under nitrogen.

The reaction is normally carried out for a time from 3 to 8 hours,suitably about 4 hours.

Suitably the phenol is employed in excess. Preferably the concentrationof phenol employed is in the range 13 to 20% w/v. The sodium orpotassium hydroxide is employed in a quantity related to the amount ofphenol used and is conveniently employed at a concentration of from 5 to8% w/v in the reaction mixture.

When the reaction is complete excess phenol is removed by conventionalmeans with a solvent and the reaction mixture is then acidified, forexample with hydrochloric or sulphuric acid, to a pH of less than 3.Preferably the pH is adjusted to 1 to 2. This acidified reaction mixtureis then extracted with a water-immiscible solvent. Examples of suitablesolvents include methyl ethyl ketone, methyl isobutyl ketone, ethylacetate, or methyl acetate, or mixtures of such solvents. A preferredsolvent is methyl isobutyl ketone.

This solvent extraction may be carried out in any conventional way,preferably by counter-current technique.

This extraction results in p-hydroxymenadelic acid being extracted intothe water-immiscible phase. The aqueous phase is discarded. The requiredsalt is precipitated from the water-immiscible solution by adding asuitable precipitating agent, depending on the particular salt. Forpreparing the sodium salt, suitable precipitating agents include sodiumhydroxide in aqueous or alcoholic solution, or sodium ethyl hexanoate ina suitable organic solvent. A solution of potassium ethyl hexanoatewould be a suitable precipitating agent for preparing the potassiumsalt. The ammonium salt may conveniently be precipitated by the additionof ammonia gas. Substituted ammonium salts can be precipitated by addingthe corresponding amine itself, or a solution, thereof.

With respect to the ammonium and substituted ammonium salts ofp-hydroxymandelic acid, these salts cannot be isolated from a reactionbetween phenol and glyoxylic acid by the salting out procedure disclosedin Belgium Pat. No. 867,287. The present invention therefore enablesthese salts to be isolated from this process for the first time.

Accordingly, this invention also provides, as novel compounds solidammonium and substituted ammonium salts of p-hydroxymandelic acid.

A preferred salt to precipitate in the process of this invention is theammonium salt, because it is precipitated the most efficiently and theaddition of ammonia gas is easy to control.

Substituted ammonium salts which may be prepared by the process of thisinvention include salts with primary, secondary or tertiary alkylamines, preferably C₁ to C₆ alkylamines, for example triethylamine,sec-butylamine, t-butylamine, and cyclohexylamine.

The salts prepared according to the process of this invention may beconverted to p-hydroxyphenylglycine by reaction with ammonia or a saltthereof as described in Belgium Pat. No. 869,021. When a substitutedammonium salt of p-hydroxymandelic acid is employed, some N-substitutedp-hydroxyphenylglycine will also be produced, and it is preferable toreact the substituted ammonium salts with the correspondinglysubstituted amine to produce an N-substituted p-hydroxyphenylglycine.

For the preparation of p-hydroxyphenylglycine itself, it is preferableto use the sodium, potassium or ammonium salt of p-hydroxymandelic acid.

The following Examples illustrate the present invention.

EXAMPLE 1 Preparation of Ammonium p-Hydroxymandelate

A mixture of phenol (1,098 g) aqueous glyoxylic acid (50% w/w solution,720 ml) and water (3 l) are stirred at 15° C. To the solution was addedsodium hydroxide solution (50% w/w) the temperature being maintained at15° C.±2° C., until the solution reached pH 10.5. The reaction mixturewas then heated to 35° C. for 3 hours.

The solution was adjusted to pH7 by addition of concentratedhydrochloric acid the temperature being maintained at 35° C. during theaddition. The mixture was extracted at 35° C. with methyl isobutylketone (2×1.2 l) to remove excess phenol.

The aqueous phase was adjusted to pH2 with concentrated hydrochloricacid and the solution temperature reduced to 20° C. The aqueous phasecontaining p-hydroxymandelic acid was continuously extracted with methylisobutyl ketone in a counter-current extractor at an organic to aqueousflow rate of 3 to 2.

After extraction, ammonia gas was passed into the stirred organic phaseuntil no more precipitation of ammonium mandelate occurred. The productwas filtered off and the ammonium mandelate cake suctioned as dry aspossible before drying under vacuum at 40° C.

Product weighed 837.5 g with an activity yield of 58.1%.

EXAMPLE 2 Preparation of Sodium p-Hydroxymandelate

The procedure of Example 1 was repeated except that the organic phasecontaining p-hydroxymandelic acid was treated with a molar equivalent ofsodium hydroxide as a 50% w/w aqueous solution. The caustic solution wasadded over one hour during which time the methyl isobutyl ketonesolution was maintained at about 20° C. with cooling. The precipitate ofsodium p-hydroxymandelate monohydrate was filtered off and suctioned asdry as possible before drying under vacuum at 40° C.

Product weighed 772.8 g, activity yield 53.5%.

EXAMPLE 3 Preparation of Ammonium p-Hydroxymandelate

Aqueous glyoxylic acid (50% w/w, 534 g) was added dropwise over 30minutes to a stirred solution of phenol (1,014 g) and sodium hydroxide(397 g) in water (4.5 l) at 35° C. The mixture was then stirred at 35°C. for 4 hours. The solution was adjusted to pH7 with concentratedhydrochloric acid the temperature being maintained at 35° C. during theaddition. The solution was extracted with methyl isobutyl ketone (3×600ml) at 35° C. to remove excess phenol. The aqueous phase was adjusted topH2 with concentrated hydrochloric acid and cooled to 20° C. The aqueousphase containing p-hydroxymandelic acid was continuously extracted withmethyl isobutyl ketone in a counter-current extraction using an organicto aqueous flow rate of 2 to 1.

After extraction, ammonia gas was passed into the organic phasecontaining the p-hydroxymandelic acid until no more precipitation ofammonium p-hydroxymandelate occurred. The solid was filtered off andsuctioned as dry as possible before drying under vacuum at 40° C.

Product weighed 578.3 g, activity yields 72.7%.

EXAMPLE 4 Preparation of Sodium p-Hydroxymandelate

Sodium hydroxide solution (50% w/w, ca 650 ml) was added dropwise overabout one hour to a stirred mixture of phenol (1.098 kg), aqueousglyoxylic acid (50% w/w solution, 720 ml) and water (3 l) at 15° C.until a pH of 10.5 had been reached. The reaction mixture was thenstirred and tested at 35° C. for 3 hours. The solution was adjusted topH7 with concentrated hydrochloric acid and extracted at 35° C. withmethyl isobutyl ketone to remove excess phenol. The aqueous solution wasadjusted to pH2 with concentrated hydrochloric acid and continuouslyextracted in a counter-current extractor with ethyl acetate at anorganic to aqueous flow rate of 1 to 1.

After extraction the organic phase was treated with a molar equivalentof a 50% w/w solution of sodium hydroxide. The resulting precipitate ofsodium p-hydroxymandelate monohydrate was stirred for 30 minutes at 20°C. and then filtered off under vacuum. The product was dried undervacuum at 40° C.

Product weighed 714.2 g, activity yield 50%.

EXAMPLE 5 Preparation of the t-Butylamine Salt of p-Hydroxymandelic Acid

Sodium hydroxide solution (50% w/w, 140 ml) was added dropwise over 20minutes to a stirred solution of phenol (183 g), aqueous glyoxylic acid(50% w/w solution, 137 ml) and water (500 ml) at between 10° C. to 15°C. The resulting mixture was then stirred at 35° C. for 7 hours. Thesolution was adjusted to pH7 with concentrated hydrochloric acid andextracted at 35° C. with methylene dichloride (1×200 ml and 2×75 ml).The solution was adjusted to pH2 with concentrated hydrochloric acid andextracted continuously in a liquid/liquid extractor with ethyl acetate(2.25 l) for 2 hours.

The resulting ethyl acetate phase was stirred and treated with an excessof t-butylamine (108 ml). The precipitate was stirred for 30 minutes andthen filtered off. The cake was washed with ethyl acetate (200 ml) andthe product, dried under vacuum at 40° C.

Weight yield of t-butylamine salt was 166.5 g.

EXAMPLE 6 Preparation of the t-Butylamine salt of p-Hydroxymandelic Acid

The procedure of Example 5 was repeated except that methyl isobutylketone was used as the extraction solvent.

The resulting methyl isobutyl ketone solution was stirred and treatedwith an excess of t-butylamine (85 ml). The precipitate was stirred for30 minutes and then filtered off. The cake was washed with MIBK (200 ml)and the product was dried under vacuum at 40° C. The weight yield oft-butylamine salt was 152 g.

EXAMPLE 7 Preparation of the Cyclohexylamine Salt of p-HydroxymandelicAcid

By the procedure of Example 6 the cyclohexylamine salt was prepared bytreating the methyl isobutyl ketone solution with an excess ofcyclohexylamine (92 ml). The weight yield of cyclohexylamine salt was168 g.

EXAMPLE 8 Preparation of the sec-Butylamine salt of p-HydroxymandelicAcid

By the procedure of Example 6 the sec-butylamine salt was prepared bytreating the methyl isobutyl ketone solution with an excess ofsec-butylamine (80 ml). The weight yield of sec-butylamine salt was149.5 g.

EXAMPLE 9 Preparation of the triethylamine salt of p-HydroxymandelicAcid

By the procedure of Example 6 the triethylamine salt was prepared bytreating the methyl isobutyl ketone solution with an excess oftriethylamine (112 ml). The solution was stirred for 30 minutes withcooling and then left to stand at 3° C. for 16 hours. The precipitatewas filtered off and the cake washed with cold methyl isobutyl ketone(200 ml). The product was dried under vacuum at 40° C. The weight yieldof triethylamine salt was 138.6 g.

EXAMPLE 10 Preparation of potassium p-Hydroxymandelate

By the procedure of Example 6 the potassium salt was prepared bytreating the methyl isobutyl ketone solution with an excess of a 2 Nsolution of potassium ethyl hexanoate in methyl isobutyl ketone (400ml). The weight yield of potassium p-hydroxymandelate was 129 g.

I claim:
 1. A process for the isolation of a solid salt ofp-hydroxymandelic acid, which process comprises reacting phenol withglyoxylic acid in the presence of sodium or potassium hydroxide,acidifying to a pH less than 3, extracting the resulting solution with awater-immiscible solvent to provide a solution of p-hydroxymandelic acidand precipitating the salt therefrom.
 2. A process as claimed in claim 1wherein the concentration of glyoxylic acid in the reaction solution isin the range of 3.5 to 7% weight-volume.
 3. A process as claimed inclaim 1, wherein the concentration of glyoxylic acid in the reactionsolution is in the range 3.5 to 4.5% weight/volume.
 4. A process asclaimed in claim 1, wherein the acidified reaction solution is extractedwith methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, methylacetate or mixtures thereof.
 5. A process as claimed in claim 4 whereinthe acidified reaction solution is extracted with methyl isobutylketone.
 6. A process as claimed in claim 1, wherein the solid salt ofp-hydroxymandelic acid is the ammonium salt.
 7. A process as claimed inclaim 6 wherein ammonium p-hydroxymandelate is precipitated by theaddition of ammonia gas.
 8. A process as claimed in claim 1, wherein thesolid salt of p-hydroxymandelic and is a substituted ammonium salt.
 9. Aprocess as claimed in claim 8 wherein the substituted ammonium salt ofp-hydroxymandelic acid is precipitated by the addition of thecorresponding amine or a solution thereof.
 10. The solid ammonium orsubstituted ammonium salt of p-hydroxymandelic acid.